EP0706401A1 - Arzneimittelsystem - Google Patents

Arzneimittelsystem

Info

Publication number
EP0706401A1
EP0706401A1 EP94918945A EP94918945A EP0706401A1 EP 0706401 A1 EP0706401 A1 EP 0706401A1 EP 94918945 A EP94918945 A EP 94918945A EP 94918945 A EP94918945 A EP 94918945A EP 0706401 A1 EP0706401 A1 EP 0706401A1
Authority
EP
European Patent Office
Prior art keywords
matrix
receptor
drug
dextran
concanavalin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP94918945A
Other languages
English (en)
French (fr)
Other versions
EP0706401B1 (de
Inventor
Margaret Joan Taylor
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
De Montfort University
Original Assignee
De Montfort University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by De Montfort University filed Critical De Montfort University
Publication of EP0706401A1 publication Critical patent/EP0706401A1/de
Application granted granted Critical
Publication of EP0706401B1 publication Critical patent/EP0706401B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2063—Proteins, e.g. gelatin

Definitions

  • This invention concerns a method for producing a drug system for delivering a drug or other agent for the treatment of a condition in a controlled release manner.
  • US 4,348,387 discloses a feedback controlled insulin delivery system wherein glucose-insulin conjugates are displaced from glucose binding sites on a binding molecule by free glucose. The conjugated insulin retains its biological activity once released. However, it is not known whether other agents or drugs can be so conjugated or whether such a conjugated form of any drug or other agent would be effective.
  • the present invention provides a delivery system for the controlled release of an unconjugated drug or other agent for .possible use in vivo.
  • a method for producing a system for delivering a drug for the treatment of a condition comprising immobilising a drug or other agent in a bio-compatible matrix containing at least one receptor for a physio ⁇ logical substance which will be in the environment of the matrix when administered, said receptor being anchored within the matrix but remaining biologically active being activated in response to the levels of said physiological substance to effect a conformational change in the matrix allowing mobilisation and release of the drug only into the environment.
  • the agent may comprise a naturally occurring biological agent, for example, a hormone, which may, of course, be insulin, as in US 4,348,387, but now in unconjugated form. Because there is now no need for conjugation, other hormones or drugs which it may not be possible to conjugate or which will not work in the system of US 4,348,387 even if they can be conjugated, or which may be physiologically ineffective or less effective or even harmful when conjugated, may be used according to the invention.
  • a naturally occurring biological agent for example, a hormone, which may, of course, be insulin, as in US 4,348,387, but now in unconjugated form. Because there is now no need for conjugation, other hormones or drugs which it may not be possible to conjugate or which will not work in the system of US 4,348,387 even if they can be conjugated, or which may be physiologically ineffective or less effective or even harmful when conjugated, may be used according to the invention.
  • the receptor may be a binding macromolecule, for example, a lectin, which may be concanavalin-A, a lectin produced from the jack bean. Because the binding macromolecule is anchored within the matrix, it is not necessary to enclose the system within a semi-permeable membrane, tube or other device, as is the case in the system of US 4,348,387. Such a method of restraining the drug system may alter the kinetics of the drug releasing mechanism and result in reduced sensitivity. Additionally, should the retaining device disintegrate, toxic lectin molecules would be released into the general circulation.
  • the present invention provides a system which overcomes these disadvantages and allows lectins to be used more safely.
  • the receptor may reversibly bind the physiological substance, which may be a carbohydrate, preferably glucose, fructose or mannose or a carbohydate polymer containing glucose moieties, such as branched starches, dextrans, mannans and levans or synthetic carbohydrates, for example, ficoll-400, a synthetic polysucrose.
  • physiological substance which may be a carbohydrate, preferably glucose, fructose or mannose or a carbohydate polymer containing glucose moieties, such as branched starches, dextrans, mannans and levans or synthetic carbohydrates, for example, ficoll-400, a synthetic polysucrose.
  • Insulin or any other agent or drug, may be immobilised in the matrix when terminal glucose molecules on dextran bind to concanavalin-A to form a gel.
  • Concanayalin-A molecules are anchored within the matrix by covalent bonding to the polymeric chains of dextran without forming insoluble aggregates. Such a system allows maintenance of the structure and function of the matrix.
  • the concanavalin-A may be covalently bonded to the dextran in any conventional manner, for example;
  • the conformational change in the matrix may be brought about by the displacement of terminal dextran-glucose molecules from the receptor by free glucose in the physiological environment which may of course be blood or other tissue fluid or fluid in the lumen of the digestive tract.
  • the conformational change may be an ungelling of the matrix allowing mobilisation and release of the insulin or other agent or drug.
  • the drug system may be specific to monosaccharides including ⁇ -D-mannose, ol ⁇ -D-glucose and c- and ⁇ -fructose and disaccharides including maltose and di-glucose with an ( ⁇ -linkage.
  • the drug system may not be affected by changes in pH from 4.0 to 8.0 nor by changes in the Mn ++ or
  • the drug system may be presented to a patient in vivo in a number of ways, for example, orally using oral hypoglycaemic drugs (insulin may not be used orally as it would not be absorbed in an active form) or by a subcutaneous implant, for example.
  • oral hypoglycaemic drugs insulin may not be used orally as it would not be absorbed in an active form
  • a subcutaneous implant for example.
  • Figure 1 shows a diagrammatical representation of a concanavalin-A molecule binding glucose
  • Figure 2 shows a diagrammatical representation of the delivery system, in an inactive form
  • Figure 3 shows a diagrammatical representation of the delivery system, in an active form; and Figures 4 to 10 show in vitro experimental results of the drug system.
  • each concanavalin-A molecule 11 has four binding sites 12 specific for sugars, with a high affinity for glucose 13 ( Figure 1).
  • the binding of glucose 13 to the binding site 12 is, however, reversible.
  • the inactive form of the drug system comprises ( Figure 2) glucose present as terminal glucose moieties 15 of the carbohydrate dextran.
  • Dextran is a branched chain polysaccharide with many terminal glucose moieties which can bind to the binding sites 12 of concanavalin-A molecules 11 and in so doing cross-link the concanavalin-A molecules together to form a viscous gel matrix.
  • Concanavalin-A molecules are covalently bonded 18 to dextran polymeric chains 14, leaving the binding sites 12 of concanavalin-A molecules 11 free to react with glucose molecules 15.
  • Insulin 16 is premixed with dextran gel, so that when concanavalin-A is added to the mixture, a gel is formed between the dextran and the concanavalin-A with the insulin immobilised inside the gel matrix much .restricted in its rate of escape ( Figure 2).
  • the binding of terminal glucose moieties of dextran to concanavalin-A is reversed ( Figure 3) when there is an increase in the concentration of free glucose 17 in the physiological environment.
  • the free glucose displaces the terminal dextran-glucose 15 from the binding sites of the concanavalin-A molecules.
  • the matrix undergoes a conformational change allowing mobilisation and release of the insulin into the environment.
  • Concanavalin-A molecules 11 remain anchored to the dextran via covalent bonds 18.
  • the displaced terminal dextran-glucose molecules will re-bind to the concanavalin-A molecules and the matrix will re-gel, thus again restricting insulin remaining in the matrix.
  • the mechanism of this drug system is thus repeatable and releases insulin in response to a number of free glucose insults, in a manner which mimics the in vivo feedback mechanism of the pancreatic cells.
  • 100 mg dextran 500,000 was made up to 0.5 g with water, allowed to hydrate and mixed well. 10 mg sodium iodate in 0.5 mg water was added, mixed and left to stand for 20 minutes. 0.5 g of an aqueous solution containing 200 mg concanavalin-A was then added, mixed until gelled and allowed to stand for 5 minutes. 0.5 g of an aqueous solution containing 10 mg sodium borohydride was added in a fume cupboard and stirred until any foam had dispersed and any yellow colouration turned white. 96% ethanol was then added dropwise until precipitation occurred and the precipitate was filtered and washed with more ethanol. The precipitate was dried and rehydrated by making up to 2 g with distilled water.
  • Precipitation was repeated a number of times. Finally, polysucrose 400 . was added to a concentration of, for example, 15% and the precipitate rehydrated by making up to 2 g with water. The 2 g samples of gel also contained 75 mg tartrazine. The gel was mixed well and stored between 4-10°C for 24 hours before use.
  • a diffusion cell was set up comprising two cellulose filters of pore size between 0.025 ⁇ m - 0.45 ⁇ m (e.g. Whatman cellulose O.l ⁇ m pore size) spaced by a ring gasket 1/8'' in thickness.
  • the gel was placed in the gap between the membranes and was made bubble free and contained a loading dose of tartrazine.
  • On one side of the cell was a reservoir containing a supersaturated solution of tartrazine (15%, above 15°C) and on the other side was a bulk solution (usually purified water) into which could be added sugar or other test additives to simulate the environment of the clinical device.
  • the bulk solution and diffusion cell were stirred and the bulk solution sampled and tested at 5 minute intervals or continuously via a flow through system.
  • Figure 5 shows the system working in response to fluctuations in the environmental glucose concentration in an attempt to mimick the situation in diabetes.
  • the bulk solution was replaced with a glucose free solution and the system monitored as before. Again there was an increased release of tartrazine from the system in the presence of glucose which was reversed in the absence of glucose.
  • Figure 6 shows the system responding to glucose concentrations between 1% and 5%. The magnitude of response does not appear to be related to the concentration used. The addition of 0.5% glucose appeared not to elicit a response.
  • Figure 7 shows the specificity of the system.
  • the system is highly specific, the flux of tartrazine responding to monosaccharides ⁇ -D-mannose, o»-D-glucose, and 0 ⁇ - and ⁇ -fructose.
  • L-glucose produced no response, there being no complementarity with the lectin receptor.
  • -D-galactose There was also no response with -D-galactose.
  • di-saccharides there is no response to lactose or cellibiose but maltose and di-glucose with an O-linkage produced a response (not shown) .
  • Figure 8 shows the response of the system to salts. No respose to the sensitivity of the system was seen with 0.3% to 1% NaCl additions to the bulk solution in the presence or absence of glucose, thus ruling out the possibilty that the gel was responding to an osmotic change.
  • Figure 9 shows the response of the system to Ca and Mn ions which are known to be required for carbohydrate binding to lectin molecules.
  • the control preparation already contained a trace of both ions but the effect of each was monitored in case it had an effect on the response.
  • Ca and Mn ions did not effect the system either alone or in combination.
  • Figure 10 shows the effect of pH on the system. pH changes from 4.0 to 8.0 had very little effect. It is assumed that the gelatinous surroundings may protect the lectin from being affected by pH as normally between pH 5.8 and 7.0 lectins exist as tetramers, while dimers and aggregates exist below and above this range respectively. Thus this system will work in the adverse pH conditions of the digestive tract.
  • the receptor may be any molecule, natural or engineered, having binding sites for complex branched substrates which would form a gel on binding, but would be displaceable by the 'free' substrate which may be naturally or artificially induced to effect release of a drug or other agent.
  • Lectins other than concanavalin-A which may be non-toxic or less toxic, may be used, for example, the pea (Pisium sativu ) lectin.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
EP94918945A 1993-06-30 1994-06-27 Arzneiverabreichungssystem Expired - Lifetime EP0706401B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9313484 1993-06-30
GB939313484A GB9313484D0 (en) 1993-06-30 1993-06-30 Drug system ii
PCT/GB1994/001384 WO1995001186A1 (en) 1993-06-30 1994-06-27 Drug system

Publications (2)

Publication Number Publication Date
EP0706401A1 true EP0706401A1 (de) 1996-04-17
EP0706401B1 EP0706401B1 (de) 2002-11-27

Family

ID=10738039

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94918945A Expired - Lifetime EP0706401B1 (de) 1993-06-30 1994-06-27 Arzneiverabreichungssystem

Country Status (11)

Country Link
US (2) US5902607A (de)
EP (1) EP0706401B1 (de)
JP (1) JP4572008B2 (de)
AT (1) ATE228374T1 (de)
AU (1) AU7004194A (de)
DE (1) DE69431800T2 (de)
DK (1) DK0706401T3 (de)
ES (1) ES2185654T3 (de)
GB (1) GB9313484D0 (de)
PT (1) PT706401E (de)
WO (1) WO1995001186A1 (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8062668B2 (en) 2002-12-17 2011-11-22 Massachusetts Institute Of Technology Stimuli-responsive systems for controlled drug delivery
WO2021113986A1 (en) * 2019-12-13 2021-06-17 Folium Labs Inc. Complexes comprising a carbohydrate polymer and an active ingredient and processes for their preparation

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9200638D0 (en) * 1992-01-10 1992-03-11 Leicester Polytechnic Drug system
GB0116860D0 (en) * 2001-07-10 2001-09-05 Univ Montfort Gel compositions
GB0412631D0 (en) * 2004-06-07 2004-07-07 Cambridge Applied Polymers Ltd Polymer release system
MX2007013725A (es) 2005-05-05 2008-04-09 Sensient Flavors Inc Produccion de beta-glucanos y mananos.
US7687608B2 (en) 2005-10-19 2010-03-30 Smartcells, Inc. Methods for reducing the mitogenicity of lectin compositions
EP2117601A2 (de) * 2006-12-22 2009-11-18 The Regents of the University of California Makromolekulare konjugate von zystische-fibrose-transmembran-leitwert-regulatorprotein-inhibitoren und verwendungen davon
WO2010088276A2 (en) * 2009-01-28 2010-08-05 Smartcells, Inc. Polynucleotide aptamer-based cross -linked materials and uses thereof
BRPI1007457A2 (pt) 2009-01-28 2015-08-25 Smartcells Inc Conjungado, formulação de liberação prolongada, e, sistema de distribuição de bomba.
WO2010088268A1 (en) 2009-01-28 2010-08-05 Smartcells, Inc. Exogenously triggered controlled release materials and uses thereof
WO2010088286A1 (en) 2009-01-28 2010-08-05 Smartcells, Inc. Synthetic conjugates and uses thereof
WO2010088300A1 (en) 2009-01-28 2010-08-05 Smartcells, Inc. Crystalline insulin-conjugates
US9095623B2 (en) * 2009-03-20 2015-08-04 Smartcells, Inc. Terminally-functionalized conjugates and uses thereof
US8623345B2 (en) 2009-03-20 2014-01-07 Smartcells Terminally-functionalized conjugates and uses thereof
WO2010107520A1 (en) 2009-03-20 2010-09-23 Smartcells, Inc. Soluble non-depot insulin conjugates and uses thereof
EP2598522A4 (de) 2010-07-28 2014-11-12 Smartcells Inc Rekombinante lektine, bindungsstellenmodifizierte lektine und anwendungen davon
AU2011282977A1 (en) 2010-07-28 2013-02-21 Smartcells, Inc. Drug-ligand conjugates, synthesis thereof, and intermediates thereto
JP2013535467A (ja) 2010-07-28 2013-09-12 スマートセルズ・インコーポレイテツド 組換えにより発現されたインスリンポリペプチドおよびその使用
US9994615B2 (en) * 2012-02-17 2018-06-12 Massachusetts Institute Of Technology Self-regulated peptide hydrogel for insulin delivery
GB201310185D0 (en) 2013-06-07 2013-07-24 Univ Montfort Container
GB201314640D0 (en) 2013-08-15 2013-10-02 Univ Montfort Matrix gel
KR20160065930A (ko) 2013-10-04 2016-06-09 머크 샤프 앤드 돔 코포레이션 글루코스-반응성 인슐린 접합체
WO2018175272A1 (en) 2017-03-23 2018-09-27 Merck Sharp & Dohme Corp. Glucose responsive insulin comprising a tri-valent sugar cluster for treatment of diabetes
US11413352B2 (en) 2017-12-18 2022-08-16 Merck, Sharp & Dohme LLC Conjugate based systems for controlled insulin delivery
EP3727424A4 (de) 2017-12-18 2021-10-27 Merck Sharp & Dohme Corp. Konjugatbasierte systeme für kontrollierte insulinfreisetzung
CN108721605B (zh) * 2018-06-01 2022-10-14 华南师范大学 一种装载有胰岛素的纳米粒子及其应用

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US4348387A (en) * 1979-07-31 1982-09-07 The Rockefeller University Method and system for the controlled release of biologically active substances to a body fluid
HK1002252A1 (en) * 1991-04-02 1998-08-07 Biotech Australia Pty. Limited Oral delivery systems for microparticles
GB9200638D0 (en) * 1992-01-10 1992-03-11 Leicester Polytechnic Drug system

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9501186A1 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8062668B2 (en) 2002-12-17 2011-11-22 Massachusetts Institute Of Technology Stimuli-responsive systems for controlled drug delivery
US8357400B2 (en) 2002-12-17 2013-01-22 Massachusetts Institute Of Technology Stimuli-responsive systems for controlled drug delivery
WO2021113986A1 (en) * 2019-12-13 2021-06-17 Folium Labs Inc. Complexes comprising a carbohydrate polymer and an active ingredient and processes for their preparation

Also Published As

Publication number Publication date
US6410053B1 (en) 2002-06-25
WO1995001186A1 (en) 1995-01-12
ES2185654T3 (es) 2003-05-01
DE69431800D1 (de) 2003-01-09
ATE228374T1 (de) 2002-12-15
AU7004194A (en) 1995-01-24
JP4572008B2 (ja) 2010-10-27
DK0706401T3 (da) 2003-03-03
US5902607A (en) 1999-05-11
EP0706401B1 (de) 2002-11-27
JPH09501416A (ja) 1997-02-10
DE69431800T2 (de) 2003-09-04
GB9313484D0 (en) 1993-08-11
PT706401E (pt) 2003-03-31

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